The broad objectives of the program are to identify genetic mechanisms underlying normal mammalian differentiation; to define the developmental changes resulting in specific genetic diseases, and to create mouse models of human diseases; and to analyze the developmental basis for certain malignancies. Genetic markers will be used as probes. They will be introduced into mouse cells with developmental potential, in three experimenatal approaches: In the first, predetermined nuclear or mitochondrial mutational changes will be incorporated into euploid, developmentally totipotent, mouse teratocarcinoma stem cells in culture, by selecting or screening mutagenized cell populations for the mutation of interest; further development of the cells will be obtained by introducing them into early embryos. Among the nuclear-gene mutants planned for study will be those coding for specific cell-surface receptors, in order to analyze receptor-mediated pathways and their ontogeny as an important feature in specialization of cell function. In a second experimental approach, exogenous recombinant cloned genes, in either native or modified form, will be introduced into mouse embryos or into cultured cells with developmental potential (e.g., teratocarcinoma cells), for the purpose of analyzing tissue-specific control of gene expression during differentiation, and to correct genetic defects. The initial emphasis in these experiments will be on globin genes and hemoglobinopathies in erythroid development. In a third approach, also centered around hematopoietic development, genetically marked pluripotent hematopoietic stem cells of embryonic or fetal origin will be introduced into early fetuses at the outset of hematopoiesis; donor-derived cells are thus processed through allogeneic host organs throughout development. These experiments are aimed at analyzing developmental lineages, cell interactions and acquisition of specificities in erythroid and lymphoid cell maturation, control of globin gene expression, and the developmental basis of defects in various mouse anemias, autoimmune disease, and strain-specific malignancies.